The compound cladribine has the following formula: ##STR1##
Cladribine is known as an antileukemic agent, i.e., in treating leukemias, such as, hairy cell leukemia and L 1210 leukemia, and as an immunosuppressive agent (D. A. Carson, D. Bruce Wasson, and Ernest Beutler, Proc. Soc. Acad. Sci. USA, Vol. 81, pp 2232-2236, 1984). More recently, cladribine has been disclosed as effective in the treatment of rheumatoid arthritis and multiple sclerosis, U.S. Pat. No. 5,310,732.
To date, cladribine has been administered by intravenous injection of saline solutions presenting two problems for subcutaneous or intramuscular injection. First, cladribine is slightly soluble in water which requires a large volume of material to be injected subcutaneously or intramuscularly to achieve the required dose. Dilute solutions are acceptable for intravenous injection, but may create pain or inflammatory difficulties for subcutaneous or intramuscular injection. Secondly, cladribine has limited stability in simple saline solutions. Stability of the compound is hampered by its tendency to undergo hydrolysis, particularly under acidic conditions. Longer shelf-life is beneficial for extended storage at refrigerated or room temperature conditions. Use of the compound orally has been limited by the fact that cladribine is acid labile and would not be stable in the acidic environment of the gastro-intestinal system.
U.S. Pat. No. 5,310,732, col. 8. teaches a 0.1 mg/mL isotonic saline solution of cladribine. There has been marketed a non-buffered solution containing 1.0 mg/mL of cladribine in 9.0 mg/mL Sodium Chloride Injection, USP.
U.S. Pat. Nos. 5,641,757 and 5,681,822 describe injectable aqueous formulations of cladribine in which the active cladribine material is solubilized with a cosolvent mixture of benzyl alcohol and propylene glycol and stabilized with m-cresol as a preservative. Use of the cosolvent mixtures disclosed therein enabled aqueous formulations of 2 to about 8 mg/ml cladribine. However, the disadvantage of these formulations lies in the danger of supersaturation and the very high osmolality of the solution. The osmolality is between 1000 and 2000 mosm while physiological osmolality is around 290 mosm. The high osmolality may result in pain and irritation when injected by the subcutaneous route. Recrystallisation of cladribine in the tissue may occur and damage the surrounding tissue.
Thus, there is a need for new formulations of cladribine which allow the subcutaneous or intramuscular injection of more concentrated aqueous solutions of cladribine which are isotonic and isohydric. Further, there is a need for oral formulations of cladribine which are stable against hydrolysis, particularly in an acid environment.
.beta.-cyclodextrin is a cyclic compound consisting of seven units of .alpha.-(1.fwdarw.4) linked D-gluco-pyranose units and is known as a complexing agent. Cyclodextrins are known in the art to possess the ability to form inclusion complexes and to have concomitant solubilizing properties. The properties of cyclodextrins and their properties have been reviewed in detail [see Szejtli, J. Cyclodextrin technology, (1988) Kluwer Academic Publishers, Dordrecht].